Systematic Literature Review of the Association of Fever and Elevated Temperature with Outcomes in Critically Ill Adult Patients

Abstract

Although most commonly associated with infection, elevated temperature and fever also occur in a variety of critically ill populations. Prior studies have suggested that fever and elevated temperature may be detrimental to critically ill patients and can lead to poor outcomes, but the evidence surrounding the association of fever with outcomes is rapidly evolving. To broadly assess potential associations of elevated temperature and fever with outcomes in critically ill adult patients, we performed a systematic literature review focusing on traumatic brain injury, stroke (ischemic and hemorrhagic), cardiac arrest, sepsis, and general intensive care unit (ICU) patients. Searches were conducted in Embase^® and PubMed^® from 2016 to 2021, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including dual-screening of abstracts, full texts, and extracted data. In total, 60 studies assessing traumatic brain injury and stroke (24), cardiac arrest (8), sepsis (22), and general ICU (6) patients were included. Mortality, functional, or neurological status and length of stay were the most frequently reported outcomes. Elevated temperature and fever were associated with poor clinical outcomes in patients with traumatic brain injury, stroke, and cardiac arrest but not in patients with sepsis. Although a causal relationship between elevated temperature and poor outcomes cannot be definitively established, the association observed in this systematic literature review supports the concept that management of elevated temperature may factor in avoidance of detrimental outcomes in multiple critically ill populations. The analysis also highlights gaps in our understanding of fever and elevated temperature in critically ill adult patients.

Introduction

Fever, the elevation of an individual's core body temperature by a regulatory mechanism, is commonly associated with infections, whereas hyperthermia is defined as elevated temperature that is not due to regulatory control (Bush and Schmidt, 2022). Fever is typically triggered by the release of proinflammatory mediators that are responsible for many of the effects and symptoms related to the febrile response (Ogoina, 2011). Up to 70% of intensive care patients may experience elevated temperature (Barie et al., 2004; Bota et al., 2004; Circiumaru et al., 1999; Kane et al., 2021; Ogoina, 2011; Sunden-Cullberg et al., 2017). In addition to being observed with sepsis in critically ill patients, fever and elevated temperature have been reported to be associated with a substantial number of noninfectious conditions in critically ill adult patients, such as stroke (ischemic and hemorrhagic), traumatic brain injury, and cardiac arrest.

Early examinations of elevated temperature and fever, particularly in cardiac arrest, suggested that hyperthermia is detrimental and can lead to poor outcomes, such as increased length of stay (LOS), worsened functional status, organ damage/failure, and potentially death (Walter et al., 2016). Similarly in stroke, fever has been associated with worse outcomes, including mortality and disability (Greer et al., 2008; Rincon et al., 2014; Saini et al., 2009). Whether fever is definitively causative of worse injury or a marker for such is unclear. A prospective study of trauma patients found no association between fever and injury severity in polytrauma or isolated body injury patients; however, fever was associated with more severe injury in isolated head injury patients (Hinson et al., 2018).

Earlier studies have looked at clinical outcomes associated with fever and elevated temperature on an indication-by-indication basis, and it is unclear if findings in specific indications are generalizable across critically ill adult patients or if elevated temperature and fever should be treated in a more indication specific manner. In this systematic literature review, we sought to investigate the association of fever and elevated temperature with clinical and economic outcomes over a broad set of indications in critically ill adult patients.

Methods

Data sources and search algorithm

This systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist (Page et al., 2021). Searches were conducted across PubMed^® (via PubMed.com) and Embase^® (via embase.com) to identify peer-reviewed articles published in the last 5 years before the search date (July 21, 2021). Articles published in the last 5 years were chosen in an attempt to capture the most up-to-date high-quality evidence. Search terms were implemented to capture relevant critically ill patient populations based on prior literature. Search terms included: critically ill, intensive care unit (ICU), cardiac arrest, traumatic brain injury, stroke (ischemic and hemorrhagic), brain hemorrhage, sepsis, mortality, neurological function, and LOS terms (Supplementary Tables S1 and S2). Search algorithms for each electronic database were designed using appropriate syntax, with combinations of medical subject headings (MeSH), Emtree terms, and free text in titles and abstracts of records.

Eligibility criteria

The populations, outcomes, and study design/eligibility criteria are described in Supplementary Table S3. Studies of elevated temperature and fever among traumatic brain injury or stroke (ischemic and hemorrhagic), cardiac arrest, sepsis, or general ICU (i.e., critically ill, not otherwise classified) patients that reported clinical or economic outcomes were included. Primary studies, such as randomized controlled trials (RCTs) and observational studies, were included for data extraction, whereas guidelines and other systematic literature reviews were included for background information only. Reference lists were hand-searched for manual additions. The systematic literature review was limited to human studies published in English in the last 5 years.

Study selection

After conducting the searches, duplicate records were removed using EndNote™ X9 (EndNote, 2013). Screening was performed in two stages according to the eligibility criteria: title and abstract screening and then full-text screening (Fig. 1 and listing of studies in Supplementary Table S4). Title and abstract screening was performed by three independent reviewers. Full-text publications were included for data extraction when at least two reviewers agreed that a citation was eligible. If full-text articles were not available for a citation, the abstract was reviewed for availability of adequate information for extraction. Both levels of screening were conducted using a web-based screening software (Covidence; Veritas Health Innovation, Melbourne, Australia). After full-text screening, a complete list of included and excluded citations was generated with reasons for exclusion at full-text screening.

FIG. 1.

Systematic literature review study identification and selection. This systematic literature review followed the PRISMA guidelines. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Data extraction

Data from included articles were extracted into a custom Microsoft^® Excel^®-based evidence grid by two researchers, and all data points were independently validated by a third researcher. Data that specifically answer the research questions of interest were extracted, including publication details, study characteristics, patient characteristics, elevated temperature definitions, and specific clinical and economic outcomes potentially impacted by fever and elevated temperature, as detailed below. Outcomes that were reported by studies as the primary or secondary endpoints were well captured in the resulting evidence grid, including mortality, functional and neurological status, and LOS, and are reported below. Additional outcomes sought by the search strategy (Supplementary Tables S1 and S2) were not captured or were insufficiently captured for reporting.

Results

Included studies and patient characteristics

The electronic database searches identified 2539 records across the 2 databases, of which 1883 were eligible for screening after de-duplication. Upon comprehensive review of all titles and abstracts, 144 records were selected for further full-text review, pending availability. From those records, this systematic literature review included 60 studies for qualitative synthesis of the literature on the relationship of fever to outcomes in critically ill adult patients (Fig. 1).

In total, 24 articles assessed traumatic brain injury or stroke (ischemic and hemorrhagic), cardiac arrest (8; including cardio-circulatory arrest), sepsis (22), and general ICU (6) patients (Supplementary Table S4) and assessed fever as a variable. The included studies were heterogeneous with respect to study design, methodology, patient populations, geographical regions, and even elevated temperature definitions. Most of the studies were observational studies (82%), and the remaining were RCTs, post hoc analyses of RCTs, registries, case–control, or chart audit studies. All studies described fever and elevated temperature within their population; however, only 70% provided the percentage or proportion with elevated temperature, and an elevated temperature definition was provided by 85% of the studies.

Studies provided elevated temperature threshold definitions that ranged from 37°C to 39°C, with the most frequent threshold being 38°C (Supplementary Fig. S1). The percentage of patients with elevated temperature, as defined within each study, ranged from 1.4% to 100%. Due to differences in definitions for fever, hyperthermia, elevated temperature, and pyrexia, the use of these terms below is based on their usage in each specific cited study.

Mortality outcomes

A total of 41 studies reported all-cause mortality outcomes for both in-hospital and longer term/out-of-hospital mortality (Table 1). In general, febrile patients with brain injury, stroke, or cardiac arrest experienced increased mortality versus nonfebrile patients, while febrile patients with sepsis had reduced mortality versus nonfebrile patients. Specific results are reported by indication below.

Table 1.

Mortality Outcomes Reported in Studies on Patients with Elevated Temperature

Authors (publication year), subgroup of patients	Outcome measure	Percentage or proportion	Odds ratio (95% CI)	Statistical significance	Comparator
Antonio et al. (2019), Bacteremia	Early case fatality	—	2.81 (1.09–7.04)	0.023	—
Antonio et al. (2019), Bacteremia	30-Day mortality	—	1.88 (0.79–4.47)	0.16	—
Armaganidis et al. (2017), ICU	ICU mortality	77%	—	—	—
Bray et al. (2017), Cardiac arrest	ICU survival	58%	—	0.31	0.71
Bray et al. (2017), Cardiac arrest	Hospital survival	58%	—	0.31	0.71
Chen and Hsu (2020), Bacteremia	30-Day mortality	40%	—	0.02	0.182
Chiodo-Reidy et al. (2020), Bacteremia	In hospital mortality	6.9%	—	0.07	0.158
Chiodo-Reidy et al. (2020), Bacteremia	30-Day mortality	10.1%	—	0.01	0.276
Covino et al. (2021), Sepsis	In hospital mortality	36.2%	—	—	—
Daniels et al. (2019), ICU	30-Day mortality	6.6%	—	—	—
De Ridder et al. (2017), Stroke	Death within 7 days	6%	—	—	0.04
De Rosa et al. (2016), Sepsis	Mortality	—	5.281 (1.542–18.080)	—	—
Di Carlo et al. (2018), Stroke	6-Month mortality	79.2%	1.7 (1.18–2.45)	0.005	—
Diktas et al. (2020), Sepsis	Fever (patients alive)	87.7%	—	0.001	0.123
Drewry et al. (2018), Sepsis	ICU mortality	11.4%	—	0.04	29.2
	Hospital mortality	15.9%	—	0.09	31.3%
	28-Day mortality	18.2%	—	0.04	37.5%
	28-Day mortality	—	0.4 (0.14–1.13)	0.08	—
Drumheller et al. (2016), Sepsis	In hospital mortality	73%	—	<0.001	50% (152/306)
Erkens et al. (2020), ICU	All-cause mortality	12%	1.8 (1.43–2.26)	0.001	7%
Erkens et al. (2020), ICU	ICU mortality	12%	1.82 (1.40–2.38)	<0.001	7%
Filbin et al. (2018), Sepsis	In hospital mortality	16%	—	<0.01	34% (84/245)
	In hospital mortality	49.8%	0.25 (0.16–0.37)	<0.01	—
	In hospital mortality	—	2.7 (1.63–4.47)	<0.01	—
	In hospital mortality	—	2.33 (1.37–3.98)	<0.01	—
Gaither et al. (2017), Traumatic brain injury	Mortality	18%	1.86 (1.15–3.00)	<0.0001	6.2%
Gao et al. (2017), Sepsis	28-Day survival	81.3%	—	0.298	0.71
Gillow et al. (2017), Traumatic brain injury	In hospital mortality	20%	—	0.014	16%
Grossestreuer et al. (2017), Cardiac arrest	Survival	—	0.25 (0.10–0.59)	0.002	—
Grossestreuer et al. (2017), Cardiac arrest	Survival	—	1.54 (1.00–2.35)	0.048	—
Henning et al. (2017), Sepsis	In hospital mortality	33%	4.3 (2.2–8.2)	—	11%
Hifumi et al. (2016), Traumatic brain injury	Mortality	34%	—	0.02	0.097
Hinson et al. (2017), Stroke	In hospital mortality	5%	—	0.09	0.3
Hinson et al. (2018), Traumatic brain injury	Mortality	6–18%	—	—	0–3%
Hu et al. (2020), Cardiac Arrest	Survival	—	0.13 (0.06–0.29)	<0.001	—
Inghammar and Sunden-Cullberg (2020), Sepsis	Mortality	17.8%	—	<0.001	0.213
Inghammar and Sunden-Cullberg (2020), Sepsis	Mortality	19.2%	—	<0.001	0.213
Khurana and Deoke (2017), ICU	Mortality	80%	—	0.08	3.4% (1/29)
Kim et al. (2018), Sepsis	In hospital mortality	6.2%	—	<0.001	42.9% (12/28)
Makker et al. (2017), Cardiac arrest	Mortality with severe rebound hyperthermia	64%	—	0.078	42%
Makker et al. (2017), Cardiac arrest	Mortality with rebound hyperthermia	50%	—	0.84	47%
Malavera et al. (2021), Stroke	Mortality	33.3%	2.44 (1.02–5.82)	0.044	11.7%
Malavera et al. (2021), Stroke	Death or major disability	71.8%	1.21 (0.49–2.95)	0.682	71.8%
Middleton et al. (2019), Stroke	Fever (dead or dependent vs. independent)	66%	0.47 (0.35–0.61)	<0.0001	0.34
Muhith et al. (2020), Stroke	Mortality	84.3%	—	—	3.9%
Nolan et al. (2021), Cardiac arrest	In hospital mortality	63.7%	—	—	61.6%
Park et al. (2020), Sepsis	In hospital mortality	8.5%	—	<0.001	0.206
Rungatscher et al. (2017), Cardio-circulatory arrest	30-Day mortality	28.6%	2.8 (1.1–8.6)	0.005	10.9%
Rungatscher et al. (2017), Cardio-circulatory arrest	In hospital mortality	25.7%	3.5 (1.8–7.5)	0.004	8.2%
Ryu et al. (2017), Cardiac arrest	ICU mortality	28%	—	—	0.35
Ryu et al. (2017), Cardiac arrest	Hospital mortality	32%	—	—	0.41
Sozio et al. (2021), Sepsis	In hospital mortality	20.1%	—	0.001	0.097
Sozio et al. (2021), Sepsis	In hospital mortality	9.7%	—	0.001
Sunden-Cullberg et al. (2017), Sepsis	In hospital mortality	36.3%	—	<0.001	37–38.29°C: 25%, 38.3–39.49°C: 20.3%, ≥39.5°C: 15.5%
Szabo et al. (2019), Sepsis	In hospital mortality	14%	—	—	—
Szabo et al. (2019), Sepsis	In hospital mortality	36.3%	—	<0.001	37–38.29°C: 25%, 38.3–39.49°C: 20.3%, ≥39.5°C: 15.5%
Wang et al. (2019), Traumatic brain injury	Mortality	1.8%	—	—	—
Xu et al. (2017), Stroke	Combined death and disability	37%	2.88	0.011	—
Young et al. (2019a), ICU	ICU mortality	25.8%	1.21 (0.57–2.55)	0.62	0.258

CI, confidence interval; ICU, intensive care unit.

Traumatic brain injury or stroke

Twelve studies reported an association between elevated temperature and mortality in patients with traumatic brain injury (five studies) or stroke (seven studies) (Table 1). The majority of the studies (11/12, 92%) found that elevated temperature and fever are significantly associated with increased mortality. One study found that hyperthermia was a significant predictor of 6-month death (hazard ratio, 1.70; 95% confidence interval [CI], 1.18–2.45) when adjusting for demographics, prestroke function, baseline diseases, and risk factors (Di Carlo et al., 2018). Muhith et al. (2020) and Hinson et al. (2017) also noted the correlation between fever and mortality in stroke and traumatic brain injury. Other studies reported increased rates of mortality when compared with patients without elevated temperature and fever (Table 1).

Cardiac and cardio-circulatory arrest

Seven studies reported an association of elevated temperature and rebound hyperthermia with mortality in patients with cardiac arrest (six studies) and cardiac surgery patients with cardio-circulatory arrest (one study). Five of the studies associated elevated temperature with significantly increased mortality, while the other two remaining studies found elevated temperature decreased or had no impact on mortality. Hyperthermia, prolonged fever, and rebound hyperthermia were all found to be associated with increased mortality (Hu et al., 2020; Makker et al., 2017; Rungatscher et al., 2017). Grossestreuer et al. (2017) reported that higher maximum temperature was associated with lower survival (adjusted odds ratio [aOR], 0.25; 95% CI, 0.10–0.59; p = 0.002) in patients who experienced post-rewarming pyrexia.

Sepsis or bacteremia

Seventeen studies examined fever and mortality in patients with sepsis or bacteremia. Multiple studies found that the absence of fever was significantly associated with mortality. Sozio et al. (2021) reported that higher temperature was associated with reduced in-hospital mortality. Other studies found that fever and elevated temperature are associated with select mortality outcomes. Antonio et al. (2019) reported mixed results in which the early case fatality rate, but not the 30-day mortality rate, was associated with low-grade fever (<38°C). De Rosa et al. (2016) found fever 48 hours after first positive cultures (odds ratio [OR] 5.281; 95% CI, 1.542–18.080) to be significantly associated with mortality. Sanderson et al. (2018) found fever to be associated with 30-day mortality (OR 0.35, 95% CI, 0.23–0.55). Another study found that inpatient mortality was not statistically different in the afebrile and febrile groups (15.8% vs. 6.9%, p = 0.070), but 30-day mortality was higher among afebrile patients (27.6% vs. 10.1%, p = 0.010) (Chiodo-Reidy et al., 2020).

General ICU

Fever and elevated temperature were generally associated with mortality, but Young et al. (2019a) found no statistically significant difference between afebrile and febrile patients. One study found that per every degree Celsius >37.5°C, the likelihood for ICU mortality increased (OR 1.82, 95% CI, 1.40–2.38; p < 0.001) (Erkens et al., 2020).

Functional and neurological outcomes

Twenty studies reported functional or neurological outcomes (Table 2). Elevated temperature and fever were generally linked to poor outcomes in patients with cardiac arrest, traumatic brain injury, or stroke, as described below.

Table 2.

Functional and Neurological Outcomes Reported in Studies on Patients with Elevated Temperature

Authors (publication year), subgroup of patients	Outcome measure	Percentage or proportion	Mean (SD)	Odds ratio (95% CI)	Median (IQR)	Statistical significance	Comparator
Alexandrov et al. (2018), Stroke	NIHSS score	—	—	—	6 (2–21.5)	0.001	2 (1–4.5)
Alexandrov et al. (2018), Stroke	mRS score	—	—	—	4	<0.001	1
Ávila-Gómez et al. (2020), Stroke	NIHSS score	—	—	0.373	—	0.001	—
Ávila-Gómez et al. (2020), Stroke	mRS score	—	—	2.19	—	0.005	—
Dehkharghani et al. (2017), Stroke	90-Day mRS score	—	—	0.31 (0.08–0.97)	—	0.056	—
De Ridder et al. (2017), Stroke	mRS score	—	—	1.02 (0.66–1.58)	—	—	—
Forlivesi et al. (2018), Stroke	No neurological improvement, hyperthermia relative to base BT in the first 12 hours	58%	—	2.88 (1.20–6.91)	—	0.018	—
Forlivesi et al. (2018), Stroke	Unfavorable functional outcome, hyperthermia relative to base BT in the first 12 hours	57%	—	3.05 (1.20–7.74)	—	0.019	—
Grossestreuer et al. (2017), Cardiac arrest	Neurological outcome, relationship of maximum temperature to outcomes, all patients	—	—	0.3 (0.10–0.84)	—	0.022	—
	Neurological outcome, relationship of maximum temperature to outcomes, OHCA patients	—	—	0.1 (0.03–0.42)	—	0.002	—
	Neurological outcome, relationship of pyrexia (38°C+) to outcomes, all patients	—	—	0.85 (0.52–1.40)	—	0.53	—
Heppekcan et al. (2019), Traumatic brain injury	Brain death	30.8%	—	—	—	0.075	0.149
Hifumi et al. (2016), Traumatic brain injury	Neurological outcome	51.1%	—	—	—	0.26	0.645
Hinson et al. (2017), Traumatic brain injury	Paroxysmal sympathetic hyperactivity	—	—	1.95 (1.12–3.40)	—	0.018	—
Huang et al. (2021), Traumatic brain injury	Glasgow Outcome Scale	—	3.3 Days	—	—	<0.001	4.6
Kim et al. (2021), Cardiac arrest	Good neurological outcome	31.6%	—	1.28 (0.925–1.772)	—	0.137	0.372
Lai et al. (2019), Stroke	mRS score 3–6	48%	—	—	—	0.01	6%
Magee et al. (2019), Stroke	mRS score	—	—	—	4 Days (3–5)	0.002	2 (1–5)
Makker et al. (2017), Cardiac arrest	Good neurological outcome	29%	—	—	—	—	0.38
Malavera et al. (2021), Stroke	Major disability	38.5%	—	0.56 (0.26–1.22)	—	0.146	41.9%
Picetti et al. (2016), Cardiac arrest	Presence of fever in patients with unfavorable neurological outcome	79.7%	—	—	—	—	0.794
Ryu et al. (2017), Cardiac arrest	Poor neurological outcomes	44%	—	—	—	—	0.47
Sakusic et al. (2018), ICU	Post-ICU cognitive impairment	—	—	9.366 (1.08–81.214)	—	—
Suehiro et al. (2016), Traumatic brain injury	Glasgow Outcome Scale	—	—	—	—	<0.05
Xu et al. (2017), Stroke	Combined death and disability	37%	—	2.88	—	0.011	—

BT, body temperature; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale/Score; OHCA, out-of-hospital cardiac arrest; SD, standard deviation.

Traumatic brain injury or stroke

Thirteen studies reported on functional and neurological outcomes in patients with traumatic brain injury (five studies) or stroke (nine studies) with elevated temperature and fever (Table 2). Multiple studies found that elevated temperature was significantly associated with poor Glasgow Outcome Scale (GOS) scores, modified Rankin Scale (mRS) scores, and Glasgow Coma Scale (GCS) scores (Table 2). Forlivesi et al. (2018) showed that ORs for no neurological improvement at 24 hours were higher in patients with hyperthermia relative to baseline/intravenous thrombolysis (OR 2.88, 95% CI, 1.20–6.91, p = 0.018) in patients with stroke.

Cardiac and cardio-circulatory arrest

Five studies reported on functional and neurological outcomes in patients with cardiac arrest with elevated temperature and fever. Many studies found that a higher maximum temperature (in the total observed time period) was significantly associated with worse neurological outcomes. In one study, after controlling for age, duration of arrest, witnessed arrest, arrest location, and initial rhythm, higher maximum temperature was associated with a worse neurological outcome (aOR 0.30; 95% CI, 0.10–0.84; p = 0.022) in patients who experienced post-rewarming pyrexia (Grossestreuer et al., 2017). Another study reported that elevated temperature is a frequent clinical occurrence following cardiac arrest and that maximum temperature during hospitalization in the ICU is significantly associated with worsened neurological outcome (Picetti et al., 2016). Ryu et al. (2017) discovered no differences in neurological outcomes between the actively controlled fever group and the normothermia group.

Sepsis or bacteremia

The association of fever and functional outcomes was not reported in the studies evaluating patients with bacteremia or sepsis.

General ICU

One study found longer duration of high fever (>39°C; OR 9.366; 95% CI, 1.08–81.214) to be independently associated with new and persistent post-ICU cognitive impairment (i.e., documented 3–24 months post-discharge) (Sakusic et al., 2018).

LOS outcomes

Sixteen studies captured LOS outcomes (Table 3). Fever and elevated temperature in patients with traumatic brain injury or stroke increased LOS, but in patients with sepsis, the LOS decreased with fever and elevated temperature.

Table 3.

Length of Stay Outcomes Reported in Studies on Patients with Elevated Temperature

Authors (publication year), subgroup of patients	Outcome measure	Percentage or proportion	Mean (SD), days	Odds ratio (95% CI)	Median (IQR)	Statistical significance	Comparator
Alexandrov et al. (2018), Stroke	LOS	—	—	—	6.4 (3.4–9.4)	<0.001	3.7 (0.7–6.7)
Drewry et al. (2018), Sepsis	ICU LOS	—	—	—	4.4 Days (3.0–7.4 days)	0.17	6.2 Days (2.9–10.5)
Filbin et al. (2018), Sepsis	ICU LOS	—	—	—	76 Hours (45–151 hours)	0.69	73 Hours (4–155)
Gaither et al. (2017), Traumatic brain injury	In hospital LOS	—	—	2.38 (1.94–2.81)	—	—	1.07
Gao et al. (2017), Sepsis	ICU	—	—	—	—	<0.05	—
Gao et al. (2017), Sepsis	ICU LOS	—	—	1.29 (1.18–1.40)	—	—	0.41
Gillow et al. (2017), Traumatic brain injury	LOS	—	13.1	—	—	<0.0001	5.1 Days
Gillow et al. (2017), Traumatic brain injury	LOS	—	15.9	—	—	<0.0001	5.8 Days
Henning et al. (2017), Sepsis	LOS	—	8.1	—	—	0.72	8.3 Days
	ICU LOS	—	3	—	—	0.79	2.8 Days
	LOS	—	6.8	—	—	0.11	4.4 Days
	ICU LOS	—	5.1	—	—	0.07	3.1 Days
Henning et al. (2017), Sepsis	LOS	—	8.1	—	—	0.72	8.3 Days
Henning et al. (2017), Sepsis	ICU LOS	—	3	—	—	0.79	2.8 Days
Hinson et al. (2018), Traumatic brain injury	ICU LOS	—	—	—	3–7 Days	—	2–3 Days
Huang et al. (2021), Traumatic brain injury	ICU LOS	—	14.75	—	—	0.001	No fever: 11.2
Huang et al. (2021), Traumatic brain injury	In hospital LOS	—	18.55	—	—	0.003	No fever: 17.4
Inghammar and Sunden-Cullberg (2020), Sepsis	LOS	—	—	—	12 Days	0.002	14 (8–24)
	LOS	—	—	—	12 Days	0.002	14 (8–24)
	LOS	—	—	—	45 Hours	0.003	54 (26–122)
	LOS	—	—	—	49 Hours	0.003	54 (26–122)
Kim et al. (2018), Sepsis	In hospital LOS	—	—	—	14 Days	0.188	19 (1–64)
Sunden-Cullberg et al. (2017), Sepsis	LOS	—	—	—	17 Days (8–34)	0.0001	37–38.29°C: 13 (7–23), 38.3–39.49°C: 11 (7–19), ≥39.5°C: 11 (6–21)
Szabo et al. (2019), Sepsis	LOS	—	—	—	10 ± 8 Days	—	—
Szabo et al. (2019), Sepsis	ICU LOS	—	—	—	8 ± 10.8 Days	—	—
Rungatscher et al. (2017), Cardio-circulatory arrest	Hospital LOS	—	—	—	21 ± 9 Days	0.5	16 ± 15
Rungatscher et al. (2017), Cardio-circulatory arrest	Hospital LOS	—	—	—	8.3 Days (4.9–12.7 days)	0.02	12.6 Days (7.4–19.2)

LOS, length of stay.

Traumatic brain injury or stroke

Five studies reported on LOS in patients with traumatic brain injury (four studies) or stroke (one study) with fever. Most studies concluded that patients with fever have significantly higher ICU and hospital LOS (Hinson et al., 2018; Huang et al., 2021). One study found there was longer LOS in patients with fever (mean days 13.1 vs. 5.1, p < 0.0001) (Table 3) (Gillow et al., 2017). Alexandrov et al. (2018) reported that poorly controlled fever was associated with significantly longer hospital LOS compared with normothermic patients who experienced a stroke.

Cardiac and cardio-circulatory arrest

The association of elevated temperature and LOS was not reported in patients with cardiac arrest. Nonsignificant longer hospital LOS was observed in hyperthermic patients following deep hypothermic circulatory arrest compared with those who remained normothermic (Rungatscher et al., 2017).

Sepsis or bacteremia

Nine studies reported on LOS in patients with sepsis or bacteremia with fever. Many of the studies reported that fever was significantly associated with shorter hospital and ICU LOS. Drewry et al. (2018) found that, compared with the afebrile group, febrile patients had significantly shorter hospital LOS (median 8.3 days [interquartile range, IQR 4.9, 12.7] vs. median 12.6 days [IQR 7.4, 19.2], p = 0.02). Similarly, other studies report that normothermia patients or patients without fever had increased LOS.

General ICU

The association of elevated temperature and LOS was not reported in general ICU patients.

Other outcomes

Ten studies reported outcomes that did not fit the criteria of mortality, functional and neurological, or LOS (Table 4). Fever was suggestive of reducing the risk of ICU admission in patients with septic shock (Jouffroy et al., 2019); however, fever correlated with secondary transfer to an intensive care setting among emergency department admissions (Cancella de Abreu et al., 2020). Fever was associated with significantly increased cost and hospital resources; in a multivariate analysis of general ICU patients, the presence of fever increased hospitalization cost by an additional €418 (p = 0.0487) (Armaganidis et al., 2017).

Table 4.

Other Outcomes Reported in Studies on Patients with Elevated Temperature

Authors (publication year), subgroup of patients	Outcome measure	Percentage or proportion	Mean (SD)	Odds ratio (95% CI)	Median (IQR)	Statistical significance	Comparator
Armaganidis et al. (2017), ICU	Mean total cost per patient	—	€22,013 (€15,500)	—	—	—	—
	Cost of LOS from start of SAT	—	10,949 (9234)	—	—	—	—
	Cost of LOS from ICU admission	—	17,787 (13,892)	—	—	—	—
Bray et al. (2017), Cardiac arrest	Patient in 36°C group, likelihood to have one temperature recording 38°C+ in first 24 hours	19%	—	—	—	0.03	0
	Patient in 36°C group, likelihood to have one temperature recording 38°C+ in first 36 hours	31%	—	—	—	0.03	0.08
Cancella de Abreu et al. (2020), ICU	Risk for secondary ICU admission	—	—	3.87 (1.21–12.35)	—	—	—
Diktas et al. (2020), Sepsis	Fever	87.7%	—	—	—	0.001	0.123
Fujii et al. (2016), Traumatic brain injury	Fever	92.06%	—	—	<0.01	7.94%	—
Jouffroy et al. (2019), Sepsis	ICU admission	—	—	0.54 (0.32–0.85)	—	0.01	—
Namikawa et al. (2019), Bacteremia	Proportion of patients with febrile neutropenia in survivor's versus non-survivors	46.2%	—	7.52 (1.70–33.1)	—	0.008	0.115
Szabo et al. (2019), Sepsis	ICU admission	27.1%	—	—	—	—	—
Wen et al. (2021), Sepsis	Sepsis diagnosis	—	—	3.66 (1.722–7.795)	—	—	—
Young et al. (2019a), ICU	ICU-free days	—	13.7 (10.5)	—	—	0.89	14 (10.6)

SAT, systemic anti-fungal therapy.

Discussion

The pathological processes of elevated temperature and fever and its presence in critically ill adult patients are widely reported in the literature, but our understanding of the outcomes associated with this condition continues to evolve. This systematic review aimed to assess the evidence base for the association of fever and elevated temperature with outcomes in multiple critical illnesses, including traumatic brain injury, stroke (ischemic and hemorrhagic), cardiac arrest, and sepsis for which a solid evidence base may exist for determining outcomes associated with elevated temperature. The potential negative association of elevated temperature and fever was frequently highlighted across the examined conditions with increased mortality, LOS, and poor functional and neurological status (Alexandrov et al., 2018; Di Carlo et al., 2018; Gillow et al., 2017; Hinson et al., 2018; Hinson et al., 2017; Huang et al., 2021; Muhith et al., 2020; Picetti et al., 2016). Whether increased morbidity is caused by fever and elevated temperature or if the febrile condition is a marker for that higher morbidity remains poorly defined.

Studies identified in our review that investigated elevated temperature and fever in patients with cardiac arrest mainly addressed the detrimental outcomes associated with rebound hyperthermia after targeted temperature management (TTM). These studies showed poor clinical outcomes associated with rebound hyperthermia in patients with cardiac arrest, supporting existing guidelines that recommend treating rebound hyperthermia with antipyretics and active cooling. The literature supporting elevated temperature avoidance for critically ill adult patients beyond cardiac arrest is less mature and thus primarily addresses the initial fever.

As Greer et al. reported in 2008, and as supported by our findings, fever demonstrated a relationship with detrimental outcomes in critically ill adult patients beyond cardiac arrest and should be properly managed (Greer et al., 2008). In patients with stroke, Thompson (2015) highlighted the importance of temperature intervention, calling for action beyond focusing on the frequency of temperature measurement or antipyretic administration. Guidelines for the care of patients with stroke support the maintenance of normothermia, but there is currently no consensus on interventions for optimal fever management (Powers et al., 2018).

In contrast to other critically ill populations, studies of patients with sepsis or bacteremia have demonstrated that fever is associated with reduced mortality and LOS. Fever may be beneficial because it increases the clearance of microorganisms, or it may be beneficial as part of the sepsis diagnosis by physicians (Launey et al., 2011). Historically, fever was a diagnostic marker for sepsis, but this criterion was removed from guidelines in 2016 (Rhodes et al., 2017). Only recently have the systemic inflammatory response syndrome (SIRS) criteria been reintroduced as a screening tool for sepsis (Evans et al., 2021).

This literature review likely captures patients evaluated under the previous diagnostic guidelines, and if elevated temperature was/is used as part of the sepsis diagnosis, patients without fever may have delayed diagnoses, inappropriate antibiotic usage, inadequate fluid resuscitation, and overall poorer quality of care. Once patients are diagnosed, controlling fever in patients with sepsis has been shown to improve oxygen consumption and overall hemodynamics (Bernard et al., 1997; Kreymann et al., 1993; Villar and Slutsky, 1993). Further studies are needed to control for practice changes due to the revisions of the sepsis criteria and to further characterize outcomes in patients with sepsis after receiving appropriate initial resuscitation.

Although the World Health Organization and the Centers for Disease Control and Prevention recognize fever as a temperature of 38°C or greater, in practice, there is no universally accepted threshold value. Elevated temperature threshold definitions among the studies included in this literature search ranged from 37°C to 39°C, with the most frequent threshold being 38°C. Although the studies in this review report body temperature, an important consideration is that brain temperature can vary widely and be as much as 15% higher than core body temperature, which may add to the importance of precisely monitoring body temperature and rapidly recognizing elevated temperature and fever in patients with traumatic brain injury or stroke (Mrozek et al., 2012). A potential solution to fever prevention and management is TTM, although the use of TTM is unclear in most disease processes outside of cardiac arrest, traumatic brain injury, and neonatal ischemic encephalopathy (Perman et al., 2014).

TTM has also encompassed application of therapeutic hypothermia, and the clinical results in studies enrolling post-cardiac arrest patients have varied considerably depending on the populations, protocols, and outcomes studied (Bernard et al., 2002; Dankiewicz et al., 2021; Lascarrou et al., 2019; Nielsen et al., 2013). Current ERC-ESICM guidelines do not take a position on hypothermic temperature control or early cooling of patients following cardiac arrest (Sandroni et al., 2022). Those current guidelines do, however, recommend preventing fever in comatose cardiac arrest patients and not actively rewarming those same patients who may be mildly hypothermic following return of spontaneous circulation.

In future research, it may be beneficial to investigate certain parameters of elevated temperature and their potential relation to clinical and economic outcomes. Beyond just the presence of elevated temperature, it is unclear if the duration of fever, the maximum temperature, or the degree of temperature fluctuation play significant roles in outcomes. A better understanding of all the dimensions of elevated temperature may facilitate optimized treatment of critically ill adult patients. For example, failure to continuously monitor patients for fever and elevated temperature can result in missed opportunities to intervene. Additionally, although few studies identified in our search reported on costs associated with elevated temperature, many studies showed changes to LOS, which may have significant cost implications.

Reported costs of care per day range from ∼$2600 per inpatient day to ∼$4300 per day in the ICU (American Hospital Association 2022; SCCM, 2022). Several studies documented the positive association of fever with improved outcomes in patients with sepsis. However, sepsis as a condition places a tremendous burden on hospitals with the mean total of care for an episode of sepsis when present upon admission being $18,023 and $51,022 when not present upon admission (Paoli et al., 2018). Likewise, fever is associated with positive outcomes in patients with bacteremia; however, the incremental cost of nosocomial bacteremia is estimated to be €15,526 (Riu et al., 2017). As noted above, changing guidelines for sepsis diagnosis may have impacted the literature assessed in this review, and future research is required to evaluate the association of fever with outcomes under current guidelines. Furthermore, additional research is required to quantify the potential impact of elevated temperature and fever on cost in critically ill adult patients.

This systematic literature review is subject to several limitations. Although there are many conditions that are considered critical illnesses, this systematic literature review focused on traumatic brain injury, stroke (ischemic and hemorrhagic), cardiac arrest, and sepsis due to the large number of patients and anticipated evidence base associated with these conditions. Another limitation is the indirect nature of the evidence. Fever and elevated temperature were described within the included studies, but the examination of the impact of this condition on outcomes was often not the primary research objective. A considerable amount of heterogeneity also existed across studies, including variations in population selection criteria, elevated temperature definitions, outcomes, and methodological approaches that precluded the application of a meta-analysis and could result in study biases. In addition, this review may be subject to publication bias (i.e., that studies finding an association between fever and outcomes are more likely to be published than finding no such association).

Conclusions

In conclusion, elevated temperature is associated with negative outcomes across many kinds of critically ill adult patients, including patients with cardiac arrest, traumatic brain injury, or stroke. Unfavorable outcomes, such as increased mortality, decreased functional status, and increased LOS, are consistently associated with the presence of fever. However, it is unclear if these associations are also present in patients with sepsis or bacteremia. Additionally, despite significant evidence on clinical outcomes, there is a limited amount of evidence on the costs and health care resource utilization of critically ill adult patients with fever and elevated temperature. Overall, these findings suggest a potential opportunity for improving patients' outcomes through improved management of body temperature. More robust studies, including factorial trials (Olsen et al., 2022; STEPCARE, 2022), are needed to fully characterize the clinical and economic impact of fever and elevated temperature.

Footnotes

Authors' Contributions

T.K., C.N., B.M., and A.P.: Conceptualization, investigation, methodology, visualization, writing—original draft, and writing—review and editing. J.R.S. and M.O.H.: Conceptualization, investigation, methodology, project administration, visualization, writing—original draft, and writing—review and editing.

Author Disclosure Statement

T.K. is an employee of Becton, Dickinson and Company (Franklin Lakes, NJ). J.R.S., M.O.H., and A.P. are employees of Trinity Life Sciences, which was engaged by Becton, Dickinson and Company for the purposes of this research. J.R.S. and M.O.H. hold equity in Trinity Life Sciences. B.M. was an employee of Trinity Life Sciences during this study and is currently employed by Boehringer Ingelheim.

Funding Information

This study was funded by Becton, Dickinson and Company.

Supplementary Material

References

Alexandrov

, Palazzo

, Biby

, et al. Back to basics: Adherence with guidelines for glucose and temperature control in an American Comprehensive Stroke Center sample. J Neurosci Nurs, 2018; 50(3):131–137.

American Hospital Association. 1999–2019 AHA Annual Survey. 2022. Available from: https://www.ahadata.com/aha-annual-survey-database [Last accessed: January 2, 2022].

Antonio

, Gudiol

, Royo-Cebrecos

, et al. Current etiology, clinical features and outcomes of bacteremia in older patients with solid tumors. J Geriatr Oncol, 2019; 10(2):246–251.

Armaganidis

, Nanas

, Antoniadou

, et al. Clinical factors affecting costs in patients receiving systemic antifungal therapy in intensive care units in Greece: Results from the ESTIMATOR study. Mycoses, 2017; 60(7):454–461.

Ávila-Gómez

, Hervella

, Da Silver-Candal

, et al. Temperature-induced changes in reperfused stroke: Inflammatory and thrombolytic biomarkers. J Clin Med, 2020; 9(7):2108.

Barie

, Hydo

, Eachempati

. Causes and consequences of fever complicating critical surgical illness. Comp Study Surg Infect, 2004; 5(2):145–159.

Bernard

, Wheeler

, Russell

, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis: The ibuprofen in sepsis study group. N Engl J Med, 1997; 336(13):912–918.

Bernard

, Gray

, Buist

, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med, 2002; 346(8):557–563.

Bota

, Ferreira

, Melot

, et al. Body temperature alterations in the critically ill. Int Care Med, 2004; 30(5):811–816.

10.

Bray

, Stub

, Bloom

, et al. Changing target temperature from 33°C to 36°C in the ICU management of out-of-hospital cardiac arrest: A before and after study. Resuscitation, 2017; 113(2017):39–43.

11.

Bush

, Schmidt

. Fever. In Merck Manual Professional Version. Merck & Co., Inc., 2022. Available from: https://www.merckmanuals.com/professional/infectious-diseases/biology-of-infectious-disease/fever [Last accessed: December 12, 2022].

12.

Cancella de Abreu

, Rousseau

, Ehrminger

, et al. Predictive factors for secondary intensive care unit admission within 48hours after hospitalization in a medical ward from the emergency room. Eur J Emerg Med, 2020; 27(3):186–192.

13.

Chen

, Hsu

. Afebrile bacteremia in adult emergency department patients with liver cirrhosis: Clinical characteristics and outcomes. Sci Rep, 2020; 10:7617.

14.

Chiodo-Reidy

, Loftus

, Holmes

. No fever, no worries? A retrospective audit of bacteraemic patients in the emergency department. Intern Med J, 2020; 52(2):282–287.

15.

Circiumaru

, Baldock

, Cohen

. A prospective study of fever in the intensive care unit. Intensive Care Med, 1999; 25(7):668–673.

16.

Covino

, Manno

, De Matteis

, et al. Prognostic role of serum procalcitonin measurement in adult patients admitted to the emergency department with fever. Antibiotics, 2021; 10:788.

17.

Daniels

, Durani

, Barreto

, et al. Impact of time to antibiotic on hospital stay, intensive care unit admission, and mortality in febrile neutropenia. Support Care Cancer, 2019; 27(11):4171–4177.

18.

Dankiewicz

, Cronberg

, Lilja

, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med, 2021; 384(24):2283–2294.

19.

De Ridder

, den Hertog

, van Gemert

, et al. PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a randomized, double-blind placebo-controlled clinical trial. Stroke, 2017; 48(4):977–982.

20.

De Rosa

, Corcione

, Motta

, et al. Risk factors for mortality in patients with Staphylococcus aureus bloodstream infection. J Chemother, 2016; 28(3):187–190.

21.

Dehkharghani

, Bowen

, Haussen

, et al. Body temperature modulates infarction growth following endovascular reperfusion. AJNR Am J Neuroradiol, 2017; 38(1):46–51.

22.

Di Carlo

, Lamassa

, Franceschini

, et al. Impact of acute-phase complications and interventions on 6-month survival after stroke. A prospective observational study. PloS One, 2018; 13(3):e0194786.

23.

Diktas

, Uysal

, Erdem

, et al. A novel ID-IRI score: Development and internal validation of the multivariable community acquired sepsis clinical risk prediction model. Eur J Clin Microbiol Infect Dis, 2020; 39(4):689–701.

24.

Drewry

, Ablordeppey

, Murray

, et al. Monocyte function and clinical outcomes in febrile and afebrile patients with severe sepsis. Shock, 2018; 50(4):381–387.

25.

Drumheller

, Agarwal

, Mikkelson

, et al. Risk factors for mortality despite early protocolized resuscitation for severe sepsis and septic shock in the emergency department. J Crit Care, 2016; 31(1):13–20.

26.

EndNote [computer program]. Version EndNote X9. Clarivate: Philadelphia, PA; 2013.

27.

Erkens

, Wernly

, Masyuk

, et al. Admission body temperature in critically ill patients as an independent risk predictor for overall outcome. Med Princ Pract, 2020; 29:389–395.

28.

Evans

, Rhodes

, Alhazzani

, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med, 2021; 47(11):1181–1247.

29.

Filbin

, Lynch

, Gillingham

, et al. Presenting symptoms independently predict mortality in septic shock: Importance of a previously unmeasured confounder. Crit Care Med, 2018; 46(10):1592–1599.

30.

Forlivesi

, Micheletti

, Tomelleri

, et al. Association of hyperglycemia, systolic and diastolic hypertension, and hyperthermia relative to baseline in the acute phase of stroke with poor outcome after intravenous thrombolysis. Blood Coagul Fibrinolysis, 2018; 29(2):167–171.

31.

Fujii

, Moriel

, Kramer

, et al. Prognostic factors of early outcome and discharge status in patients undergoing surgical intervention following traumatic intracranial hemorrhage. J Clin Neurosci, 2016; 31(2016):152–156.

32.

Gaither

, Chikani

, Stolz

, et al. Body temperature after EMS transport: Association with traumatic brain injury outcomes. Prehosp Emerg Care, 2017; 21(5):575–582.

33.

Gao

, Zhu

, Yin

, et al. Effects of target temperature management on the outcome of septic patients with fever. Biomed Res Int, 2017; 2017:3906032.

34.

Gillow

, Ouyang

, Lee

, et al. Factors associated with fever in intracerebral hemorrhage. J Stroke Cerebrovasc Dis, 2017; 26(6):1204–1208.

35.

Greer

, Funk

, Reaven

, et al. Impact of fever on outcome in patients with stroke and neurologic injury: A comprehensive meta-analysis. Stroke, 2008; 39(11):3029–3035.

36.

Grossestreuer

, Gaieski

, Donnino

, et al. Magnitude of temperature elevation is associated with neurologic and survival outcomes in resuscitated cardiac arrest patients with postrewarming pyrexia. J Crit Care, 2017; 38:78–83.

37.

Henning

, Carey

, Oedorf

, et al. The absence of fever is associated with higher mortality and decreased antibiotic and iv fluid administration in emergency department patients with suspected septic shock. Crit Care Med, 2017; 45:e575–e582.

38.

Heppekcan

, Ekin

, Civi

, et al. Impact of secondary insults in brain death after traumatic brain injury. Transplant Proc, 2019; 51(7):2186–2188.

39.

Hifumi

, Kuroda

, Kawakita

, et al. Fever control management is preferable to mild therapeutic hypothermia in traumatic brain injury patients with abbreviated injury scale 3–4: A multi-center, randomized controlled trial. J Neurotrauma, 2016; 33:1047–1053.

40.

Hinson

, Rowell

, Morris

, et al. Early fever after trauma: Does it matter?. J Trauma Acute Care Surg, 2018; 84(1):19–24.

41.

Hinson

, Schreiber

, Laurie

, et al. Early fever as a predictor of paroxysmal sympathetic hyperactivity in traumatic brain injury. J Head Trauma Rehabil, 2017; 32(5):E50–E54.

42.

, Guo

, Wang

, et al. Effects of the incidence density of fever (IDF) on patients resuscitated from in-hospital cardiac arrest: A mediation analysis. Front Med (Lausanne), 2020; 7:86.

43.

Huang

, Wang

, Wu

, et al. Post-craniotomy fever and its associated factors in patients with traumatic brain injury. Nurs Crit Care, 2021; 27(4):483–492.

44.

Inghammar

, Sunden-Cullberg

. Prognostic significance of body temperature in the emergency department vs the ICU in Patients with severe sepsis or septic shock: A nationwide cohort study. PloS One, 2020; 15(12):e0243990.

45.

Jouffroy

, Saade

, Durand

, et al. Predicting value of prehospital body temperature for ICU admission of septic shock patients. Acute Med, 2019; 18(1):56–58.

46.

Kane

, Hassinger

, Elwood

, et al. Fever is associated with reduced mortality in trauma and surgical intensive care unit-acquired infections. Surg Infect, 2021; 22(2):174–181.

47.

Khurana

, Deoke

. Thrombocytopenia in critically ill patients: Clinical and laboratorial behavior and its correlation with short-term outcome during hospitalization. Indian J Crit Care Med, 2017; 21(12):861–864.

48.

Kim

, Lee

, Park

, et al. Impact of controlled normothermia following hypothermic targeted temperature management for post-rewarming fever and outcomes in post-cardiac arrest patients: A propensity score-matched analysis from a multicentre registry. Resuscitation, 2021; 162(2021):284–291.

49.

Kim

, Kim

, Yu

, et al. Association between afebrile status and in-hospital mortality among adult chronic hemodialysis patients with bacteremia. Hemodial Int, 2018; 22(1):119–125.

50.

Kreymann

, Grosser

, Buggisch

, et al. Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock. Crit Care Med, 1993; 21(7):1012–1019.

51.

Lai

PMR

, See

, Silva

, et al. Noninfectious fever in aneurysmal subarachnoid hemorrhage: Association with cerebral vasospasm and clinical outcome. World Neurosurg, 2019; 122:e1014–e1019.

52.

Lascarrou

, Merdji

, Le Gouge

, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med, 2019; 381(24):2327–2337.

53.

Launey

, Nesseler

, Mallédant

, et al. Clinical review: Fever in septic ICU patients—Friend or foe?. Crit Care, 2011; 15(3):222.

54.

Magee

, Bastin

MLT

, Graves

, et al. Fever burden in patients with subarachnoid hemorrhage and the increased use of antibiotics. J Stroke Cerebrovasc Dis, 2019; 28(11):104313.

55.

Makker

, Shimada

, Misra

, et al. Clinical effect of rebound hyperthermia after cooling postcardiac arrest: A retrospective cohort study. Ther Hypothermia Temp Manag, 2017; 7(3):137–140.

56.

Malavera

, You

, Zheng

, et al. Prognostic significance of early pyrexia in acute intracerebral haemorrhage: The INTERACT2 study. J Neurol Sci, 2021; 423(2021):117364.

57.

Middleton

, McElduff

, Drury

, et al. Vital sign monitoring following stroke associated with 90-day independence: A secondary analysis of the QASC cluster randomized trial. Int J Nurs Stud, 2019; 89:72–79.

58.

Mrozek

, Vardon

, Geeraerts

. Brain temperature: Physiology and pathophysiology after brain injury. Anesthesiol Res Pract, 2012; 2012:989487.

59.

Muhith

, Herlambang

, Haryuni

, et al. Body Temperature, Glasgow Coma Scale (GCS) and mortality of patients with intracerebral hemorrhage stroke. SRP, 2020; 11(7):224–227.

60.

Namikawa

, Yamada

, Yamairi

, et al. Mortality caused by extended-spectrum beta-lactamase–producing Enterobacteriaceae bacteremia; a case control study: Alert to Enterobacteriaceae strains with high minimum inhibitory concentrations of piperacillin/tazobactam. Diagn Microbiol Infect Dis, 2019; 94(3):287–292.

61.

Nielsen

, Wetterslev

, Cronberg

, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med, 2013; 369(23):2197–2206.

62.

Nolan

, Orzechowska

, Harrison

, et al. Changes in temperature management and outcome after out-of-hospital cardiac arrest in United Kingdom intensive care units following publication of the targeted temperature management trial. Resuscitation, 2021; 162(2021):304–311.

63.

Ogoina

. Fever, fever patterns and diseases called ‘fever’—A review. J Infect Public Health, 2011; 4(3):108–124.

64.

Olsen

, Jensen

AKG

, Dankiewicz

, et al. Interactions in the 2 × 2 × 2 factorial randomised clinical STEPCARE trial and the potential effects on conclusions: A protocol for a simulation study. Trials, 2022; 23(1):889.

65.

Page

, McKenzie

, Bossuyt

, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, 2021; 372:n71.

66.

Paoli

, Reynolds

, Sinha

, et al. Epidemiology and costs of sepsis in the United States-an analysis based on timing of diagnosis and severity level. Crit Care Med, 2018; 46(12):1889–1897.

67.

Park

, Jeon

, Oh

, et al. Normothermia in patients with sepsis who present to emergency departments is associated with low compliance with sepsis bundles and increased in-hospital mortality rate. Crit Care Med, 2020; 48(10):1462–1470.

68.

Perman

, Goyal

, Neumar

, et al. Clinical applications of targeted temperature management. Chest, 2014; 145(2):386–393.

69.

Picetti

, Antonini

, Bartolini

, et al. Delayed fever and neurological outcome after cardiac arrest: A retrospective clinical study. Neurocrit Care, 2016; 24(2):163–171.

70.

Powers

, Rabinstein

, Ackerson

, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2018; 49(3):e46–e110.

71.

Rahmig

, Kuhn

, Neugebauer

, et al. Normothermia after decompressive surgery for space-occupying middle cerebral artery infarction: A protocol-based approach. BMC Neurol, 2017; 17:205.

72.

Rhodes

, Evans

, Alhazzani

, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med, 2017; 43(3):304–377.

73.

Rincon

, Hunter

, Schorr

, et al. The epidemiology of spontaneous fever and hypothermia on admission of brain injury patients to intensive care units: A multicenter cohort study. J Neurosurg, 2014; 121:950–960.

74.

Riu

, Chiarello

, Terradas

, et al. Incremental cost of nosocomial bacteremia according to the focus of infection and antibiotic sensitivity of the causative microorganism in a university hospital. Medicine (Baltimore), 2017; 96(17):e6645.

75.

Rungatscher

, Luciani

, Linardi

, et al. Temperature variation after rewarming from deep hypothermic circulatory arrest is associated with survival and neurologic outcome. Ther Hypothermia Temp Manag, 2017; 7(2):101–106.

76.

Ryu

, Park

, Chung

, et al. Association between body temperature patterns and neurological outcomes after extracorporeal cardiopulmonary resuscitation. PloS One, 2017; 12(1):e0170711.

77.

Saini

, Saqqur

, Kamruzzaman

, et al. Effect of hyperthermia on prognosis after acute ischemic stroke. Stroke, 2009; 40:3051–3059.

78.

Sakusic

, Gajic

, Singh

, et al. Risk factors for persistent cognitive impairment after critical illness, nested case-control study. Crit Care Med, 2018; 46(12):1977–1984.

79.

Sanderson

, Chikhani

, Blyth

, et al. Predicting 30-day mortality in patients with sepsis: An exploratory analysis of process of care and patient characteristics. J Intensive Care Soc, 2018; 19(4):299–304.

80.

Sandroni

, Nolan

, Andersen

, et al. ERC-ESICM guidelines on temperature control after cardiac arrest in adults. Intensive Care Med, 2022; 48(3):261–269.

81.

Sedation, Temperature and Pressure After Cardiac Arrest and Resuscitation (STEPCARE). ClinicalTrials.gov identifier NCT05564754. Updated October 3, 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT05564754 [Last accessed February 22, 2023].

82.

Society of Critical Care Medicine (SCCM). SCCM: Critical Care Statistics. 2022. Available from: https://www.sccm.org/Communications/Critical-Care-Statistics [Last accessed: January 2, 2022].

83.

Sozio

, Bertini

, Bertolino

, et al. Recognition in emergency department of septic patients at higher risk of death: Beware of patients without fever. Medicina (Kaunas), 2021; 57(6):612.

84.

Suehiro

, Sadahiro

, Goto

, et al. Importance of early postoperative body temperature management for treatment of subarachnoid hemorrhage. J Strok Cerebrovas Dis, 2016; 25(6):1482–1488.

85.

Sunden-Cullberg

, Rylance

, Svefors

, et al. Fever in the emergency department predicts survival of patient with severe sepsis and septic shock admitted to the ICU. Crit Care Med, 2017; 45(4):591–599.

86.

Szabo

, Kiss

, Lenart

, et al. Clinical and microbiological characteristics and outcomes of community-acquired sepsis among adults: A single center, 1-year retrospective observational cohort study from Hungary. BMC Infect Dis, 2019; 19:584.

87.

Thompson

. Evidence-base for fever interventions following stroke. Stroke, 2015; 46(5):e98–e100.

88.

Veritas Health

Innovation

, Melbourne

Australia

. Covidence Systematic Review Software. 2022. Available from: www.covidence.org [Last accessed: April 18, 2023].

89.

Villar

, Slutsky

. Effects of induced hypothermia in patients with septic adult respiratory distress syndrome. Resuscitation, 1993; 26(2):183–192.

90.

Walter

, Hanna-Jumma

, Carraretto

, et al. The pathophysiological basis and consequences of fever. Crit Care, 2016; 20(1):200.

91.

Wang

, Ma

, Zhao

, et al. Risk factors of hospital mortality in chronic subdural hematoma: A retrospective analysis of 1117 patients, a single institute experience. J Clin Neurosci, 2019; 67(2019):46–51.

92.

Wen

, Chen

, Ming

, et al. Analysis of risk factors, pathogenic bacteria of maternal sepsis in term pregnant women with positive blood culture during hospitalization. Medicine, 2021; 100:7.

93.

, Hackett

, Chalmers

, et al. Frequency, determinants, and effects of early seizures after thrombolysis for acute ischemic stroke: The ENCHANTED trial. Neurol Clin Pract, 2017; 7(4):324–332.

94.

Young

, Bailey

, Bass

, et al. Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial. Intensive Care Med, 2019a;45(10):1382–1391.

95.

Young

, Bellomo

, Bernard

, et al. Fever control in critically ill adults. An individual patient data meta-analysis of randomized controlled trials. Int Care Med, 2019b;45(4):468–476.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.08 MB

0.01 MB

0.04 MB

0.00 MB